This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Although highly active anti-retroviral therapy (HAART) has markedly reduced the morbidity and mortality of HIV-infected children, the improved life expectancy is associated with a complex set of metabolic disorders in a subset of patients. These disorders include growth failure with lower lean body mass (LBM). Although the clinical features of this metabolic derangement is described, its mechanistic underpinnings are unknown. It is important to delineate these mechanisms in order to establish new therapies for pediatric patients because growth failure will lead to stunting. In this project we plan to test the hypothesis that HIV-infected children have a lower LBM due to a deficit in net protein synthesis because of upregulated protein catabolism. To test this hypothesis we propose to conduct stable isotope tracer experiments to achieve the following specific aim: measure lean body mass (LBM) and protein kinetics in HIV-infected prepubertal children versus age-and gender-matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on LBM and protein kinetics in the HIV-infected group. I. HYPOTHESIS Despite an adequate dietary protein intake, HIV-infected children have a lower LBM due to a deficit in the availability of endogenous protein to support LBM synthesis. This decreased protein availability is secondary to a chronic upregulation of protein catabolism relative to intake. We further propose that this condition can be ameliorated by dietary supplementation with more energy and protein. II. SPECIFIC AIM Measure body composition and protein kinetics in prepubertal HIV-infected children versus age and gender matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on protein kinetics in the HIV-infected group. III. BACKGROUND AND SIGNIFICANCE Although loss of lean body mass (LBM) is a common finding in adults with acquired immunodeficiency syndrome (AIDS), it is not a common finding in asymptomatic HIV-infected adults, that is, those without secondary infections (1,2). Studies in such patients, like those in patients with other stressed states, show faster rates of whole body protein turnover than observed in healthy controls. Dietary protein intake and net rates of protein catabolism, however, are similar to those observed in healthy controls. Hence, protein balance is maintained in HIV-infected adults (1,2). In contrast, growth failure secondary to low rates of lean tissue deposition is common in infants and young children with HIV infection, including those without secondary infections (3-5). There is evidence that both linear and ponderal growth are affected (6-8) and in a retrospective study, Arpadi reported that 42% of perinatally HIV-infected children had a growth velocity below the fifth percentile, indicating growth failure (8). Thus, it appears that the virus, per se, induces a disturbance in protein metabolism that leads to reduced protein deposition in infants and young children but not in adults. Indeed there is evidence that levels of HIV RNA are greater in children with poor growth compared with infected children with normal rates of growth, suggesting that suppression of HIV replication should have positive effects on growth. This has been confirmed by recent reports showing that HAART has positive effects on both weight and linear growth velocity, especially among younger children (9-11). What is not clear is whether improved growth is associated with improved net protein synthesis, hence increased LBM. Whereas, Miller et al reported an 11.5% improvement in arm muscle circumference in a cohort of ~9 year old HIV-infected children who were on HAART for 7-10 months (9), Verweel et al reported that body mass index (BMI) did not increase in all children treated with HAART (11). It only improved in children who were undernourished at baseline prior to starting HAART. On the other hand, one study of 197 children aged 2 to 17 years randomly assigned to ritonavir containing regimens reported a worsening of growth in those children who achieved and maintained HIV-1 RNA levels at and below 400 copies/mL after 48 to 96 weeks (12). To resolve these conflicting findings it is necessary to measure in vivo protein kinetics in HIV-infected children. Significance In HIV-infected children growth failure is an important predictor of a poor prognosis. It is well established that growth failure often precedes secondary infections in HIV-infected infants and children (e.g. 3-5) indicating that inadequate protein deposition may be an early manifestation of infection by the virus. However, little is known about protein metabolism of HIV-infected infants and young children. Based on our preliminary findings in asymptomatic HIV-infected children (13), we propose that infection by the virus elicits an acute phase response. Hence, more protein and energy has to be channeled towards sustaining increased turnover of acute phase proteins in the face of reduced dietary energy and inefficient utilization of dietary protein. Based on these data we propose that a reduction of viral load by HAART plus a diet supplemented with extra energy and protein should abolish the lower net protein synthesis of HIV-infected children, thereby increasing growth and LBM.